Opioid Use in Pregnancy Linked to Birth Defects

March 10, 2011 — Opioid use just before conception or in early pregnancy has been associated with an increased risk for birth defects, including hypoplastic left heart syndrome, one of the most critical heart defects.According to an ongoing, population-based study conducted by the Centers for Disease Control and Prevention (CDC), women receiving opioid analgesic treatment in early pregnancy had a 2- to 3-fold increased risk of delivering infants with conoventricular septal defects, atrioventricular septal defects, hypoplastic left heart syndrome, spina bifida, or gastroschisis."It's important to acknowledge that although there is an increased risk for some types of major birth defects from an exposure to opioid analgesics, that absolute risk for any individual woman is relatively modest," principal investigator Cheryl S. Broussard, PhD, from the CDC's National Center on Birth Defects and Developmental Disabilities, said in a news release."However, with very serious and life-threatening birth defects like hypoplastic left heart syndrome, the prevention of even a small number of cases is very important," she said.The study was published online February 24 in the American Journal of Obstetrics and Gynecology.

Leading Cause of Death

According to the study authors, previous research has shown that opioid analgesic use and abuse have been increasing in recent years but their effects on the developing fetus are poorly understood.Studies that looked at their potential effects have been plagued by insufficient sample sizes and inconsistent results.Major birth defects affect about 3% of the 4 million live births each year in the United States and are the leading cause of infant deaths, the study team notes. Congenital heart defects are the most common type of birth defect, affecting nearly 1% of US births, and are the main contributor to infant mortality attributable to birth defects."Despite evidence of adverse fetal effects with maternal codeine use and the paucity of data on the effects of maternal use of other opioids, such treatment is often assumed to be safe during pregnancy," the study authors note.To examine whether maternal therapeutic use of opioid analgesics in early pregnancy is associated with birth defects, the investigators analyzed data from the National Birth Defects Prevention Study, an ongoing, population-based, case-control study for infants born October 1, 1997, through December 31, 2005, in 10 states.This study focuses on infants with birth defects of unknown causes, so those with recognized chromosomal abnormalities or single-gene disorders are excluded.

Risk-Benefit Must Be Weighed

Mothers were interviewed between 6 weeks and 2 years after the estimated date of delivery and queried about various maternal health factors, pregnancy history information, dietary and drug exposures, and sociodemographic characteristics.Exposures were assessed for the period from 3 months before conception through the end of pregnancy.The researchers defined opioid exposure as maternal report of one or more opioids taken for therapeutic reasons. These included codeine, hydrocodone, meperidine, oxycodone, propoxyphene, morphine, tramadol, methadone, hydromorphone, fentanyl, or pentazocine. The exposure window of interest was the period from 1 month before to 3 months after conception.The investigators found that therapeutic opioid use was reported by 2.6% of 17,449 case mothers and 2.0% of 6701 control mothers. The most commonly prescribed opioids included codeine (34.5%), hydrocodone (34.5%), oxycodone (14.4%), and meperidine (12.9%).Codeine and hydrocodone exposure were slightly more common among cases, and oxycodone and meperidine were slightly more common among controls.Treatment was statistically significantly associated with conoventricular septal defects (odds ratio [OR], 2.7; 95% confidence interval [CI], 1.1 – 6.3), atrioventricular septal defects (OR, 2.0; 95% CI, 1.2 – 3.6), hypoplastic left heart syndrome (OR, 2.4; 95% CI, 1.4 – 4.1), spina bifida (OR, 2.0; 95% CI, 1.3 – 3.2), or gastroschisis (OR, 1.8; 95% CI, 1.1 – 2.9) in infants, the investigators report.Codeine and hydrocodone accounted for most of the statistically significant findings, the study authors note, but these drugs were also the most commonly used, representing 69% of all reported exposures.It's possible, the study authors say, that some of the findings may be due to chance. "Our results should be treated with caution and deserve further investigation," they write.They did not have information on medication dose so were unable to assess dose-response relationships. In addition, illicit drug use was not assessed."It is critical that health care providers weigh the benefits of these medications along with their potential risks when discussing analgesic treatment options with patients who are or may become pregnant, including reproductive-aged women who are not planning a pregnancy but might be at risk of an unintended pregnancy," the study authors write.The study authors have disclosed no relevant financial relationships.

Am J Obstet Gynecol. Published online February 24, 2011. Abstract

Clinical Context

Major birth defects affect approximately 3% of the 3 million US live births each year, and congenital heart defects are common and affect nearly 1% of births as a main contributor to infant mortality. Opioids are often prescribed with nonopioid analgesics in women before conception, and it is unclear if maternal therapeutic use is associated with congenital heart defects and other congenital defects.This is a case-control, population-based study of live births to examine the role of maternal opioids in congenital heart defects and other birth defects.

Study Highlights

Included were infants born between 1997 and 2005 in the National Birth Defects Prevention Study, a multisite population-based, case-control study of more than 30 types of major structural birth defects focusing on exposures immediately before and during pregnancy.

Excluded were known chromosomal abnormalities, single gene disorders, noncardiac and nonstructural defects, and physiologic rather than structural defects such as patent foramen ovale.

Control infants were infants of mothers who did not have birth defects born in the same period and from the same region or states.

Mothers participated in structured telephone interviews between 6 weeks and 2 years after birth, with average of 11 months after delivery for cases and 9 months for controls.

Mothers were asked about medication use for each specific illness or indication, such as surgery. They were also asked to report start and stop dates, duration and frequency of opioid use, and calendar dates or pregnancy months.

Logistic regression was used to calculate ORs for birth defects.

Of 17,449 mothers of case infants, 2.6% reported analgesic opioid use between 1 month before and 3 months after conception.

Limiting the exposure definition to the first 2 months after conception produced similar results.

The authors concluded that opioid use before and after conception was associated with an increased risk for congenital heart defects and noncardiac birth defects.

They urged caution in considering use of opioids among women of reproductive age who may become pregnant.

Clinical Implications

Maternal use of opioids 1 month before to 3 months after conception is associated with an increased risk for congenital heart defects.

Maternal use of opioids 1 month before to 3 months after conception is associated with an increased risk for noncardiac birth defects, such as spina bifida, hydrocephaly, anterior chamber eye defects, and gastroschisis.